News Release

LA JOLLA, CA – December 9, 2011 – New research by scientists
at The Scripps Research Institute has underlined the power of an endogenous anti-stress
peptide in the brain to prevent and even reverse some of the cellular effects
of acute alcohol and alcohol dependence in animal models. The work could lead
to the development of novel drugs to treat alcoholism.

The new study, led by Scripps Research Associate Professor
Marisa Roberto and now published online ahead of print by the journal Biological Psychiatry, illuminates the
cellular mechanisms that govern the transition from alcohol use to alcohol
dependence. Specifically, the study examined the interaction between two
competing agents—one a stress peptide that promotes excessive alcohol drinking,
the other an anti-stress peptide that opposes it. The results confirm that
drugs derived from the anti-stress peptide nociceptin could play an important
role in treating a complex and multi-faceted disease.

"Alcohol affects a lot of systems in the brain, and
there won't be a single pill that will cure the multiple and complex aspects of
this disease," Roberto said. Instead, scientists are seeking to attack the
disease from a variety of angles, and are investigating the many different
areas of the brain that appear to play a role in the use and abuse of alcohol.

Alcoholism, a chronic disease characterized by compulsive
drinking and loss of control over alcohol intake, is devastating to both individuals
and society. Approximately one third of all traffic fatalities involve drunk
drivers, and alcohol abuse generates hundreds of billions of dollars in direct
and indirect public health costs.

"Alcoholism is a complex disorder with many
contributing factors, one of which is stress,” said
Maureen Cruz, a research associate in Roberto’s lab and first author of the
study. "By targeting a particular system that's associated with stress, we
can better understand the interaction of alcohol and stress in the brain."

Peptide vs. Peptide

Roberto and her team focus on the central nucleus of the
amygdala, a region of the brain that has long been implicated in the elevated
anxiety and excessive drinking associated with alcohol dependence and
withdrawal.

In previous animal studies, Roberto and her colleagues
demonstrated that a particular stress peptide produced in the amygdala,
corticotropin-releasing factor (CRF), plays a key role in the transition from
alcohol use to alcohol dependence. "This peptide," said Roberto,
"drives craving for alcohol." Roberto and her colleagues also
demonstrated that nociceptin, a peptide that structurally resembles endogenous
opioids, can both prevent and reverse some effects of alcohol.

Intriguingly, CRF and nociceptin exert opposite effects on
the inhibitory neurotransmitter, gamma-amino butyric acid (GABA), in central
amygdala. CRF stimulates the release of GABA by neurons in the amygdala, while
nociceptin inhibits it.

In the new study, Roberto, Cruz, and their colleagues examined
how these two competing agents interact. At the behavioral level, nociceptin
regulates anxiety and alcohol drinking in rats. "We were interested in
seeing if nociceptin blocked the effect of CRF on a cellular level," Roberto
said.

To find out if that were indeed the case, the scientists examined
amygdala neurons from both alcohol-dependent and control rats. They added CRF
and nociceptin and electrically stimulated the neurons to see how they would
behave under the influence of both peptides. The result: nociceptin completely
blocked the effects of CRF on GABA release.

Winner Takes All

But that was not all. By varying the sequence in which the
scientists introduced the two opposing peptides, the researchers established
that it did not matter whether they introduced nociceptin before or after CRF
had done its work: In either case, nociceptin counteracted CRF and drove GABA
levels down. "No matter when CRF is added, nociceptin wins," said
Roberto. "That's a really consistent effect."

The researchers also found that both CRF and nociceptin had
a more powerful effect on the amygdala neurons of alcohol-dependent rats
compared to those from non-dependent animals. Roberto believes that this has to
do with cellular changes that alcohol dependence causes in the brain—changes
that heighten sensitivity to alcohol, compounding the effects of both drinking
and withdrawal.

In addition, the team was able to determine that nociceptin
and CRF both rely on the same enzyme, protein kinase A (PKA), to modulate GABA release
in the amygdala.

In addition to Roberto and Cruz, the authors of the Biological Psychiatry paper, titled
"Nociceptin/Orphanin FQ Blockade of CRF-induced GABA
Release in Central Amygdala is Enhanced after Chronic Ethanol Exposure,"
include Melissa A. Herman and Marsida Kallupi of Scripps Research. See http://www.sciencedirect.com/science/article/pii/S0006322311010791.

Support for the study came from the Pearson Center for Alcoholism and Addiction Research and the
National Institute on Alcohol Abuse and Alcoholism.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.